POS0346 IDENTIFICATION OF NEW MUTATIONS IN THE SQSMT1 GENE IN PATIENTS WITH PAGET’S DISEASE OF BONE. GENOTYPE-PHENOTYPE CORRELATION
Authors: A. Conesa, N. García Giralt, D. Bedoya Sanchis, M. Á. Belmonte Serrano
Journal: Annals of the Rheumatic Diseases (2022)

Background The Paget’s disease of Bone (PDB) is characterized by a chronic and focal disorder of bone remodeling. PDB is currently considered a complex and multifactorial disease, as a result of a synergistic association of genetic variants with environmental risk factors. The genetic component would explain certain epidemiological traits such as the predisposition to develop in certain ethnic groups and the strong tendency to family aggregation. The most important susceptibility gene for PDB is the Sequestosome-1 ( SQSTM1 ), and encodes a 440-amino-acid protein called p62 protein. SQSTM1 gene occur in between 20 and 40% of patients with a family history of PDB, and 5 and 10% of patients with ‘sporadic’ disease, according to the series studied. Thus far, 29 SQSTM1 mutations have been identified in patients with PDB 1-4 . Objectives To analyze the importance of SQSTM1 gene (p62) variants in the susceptibility to develop PDB, as well as to evaluate the genotype-phenotype correlation in our PDB population. Methods The molecular study was carried out by sequencing the SQSTM1 gene (p62) in a population of 200 PDB affected patients and 200 hypernormal controls. An “ in silico ” functional analysis of the different genetic variants was performed using the information provided by the splicing prediction algorithms, the miRNA target prediction algorithms, the gene-specific algorithms for predicting pathogenicity (SIFT, PolyPhen, PMut) and the interspecific evolutionary conservation study. The statistical analysis was performed using SPSS statistical software Windows (v23) and the R software version 2.15.0 for Windows. The study was approved by the CEIC (Hospital del Mar-Parc de Salut Mar (2007/2885/I)) and all participants signed an informed consent agreeing to participate in the study. Results The 27% of the PDB affected patients were carriers of different gene SQSMT1 mutations, being the most frequent identified the p.P392L, described in the 20% of cases. In terms of genotype-phenotype relation, being a carrier of gene SQSMT1 mutations is associated to a more severe phenotype based on a greater disease activity and a greater extent at diagnosis as well as higher complications during the course of it, without the presence of an associated family history positive. In our patient cohort 17 mutations have been identified in coding regions of the SQSMT1, with six newly described “ missense ” genetic variants (p.R161W, p.H163Y, p.K238E, p.G262R, p.E274D,p.G405S), all of them associated to a greater susceptibility in the development of PDB and distributed in the different structural and functional domains of the p62 protein, being able to cause dysfuntions in the different cell signalling processes where intervenes (apoptosis, autophagy, proteic degradation through the ubiquitin-proteasome system, the regulation of antioxidant response and the cell survival mediated by RANK-TRAF6-NF-κB signaling pathway), implicated in the pathogenesis of Paget’s disease of bone. Conclusion In the molecular study of the SQSTM1 gene, seventeen mutations were identified in the coding regions of the gene, being six “ missense ” genetic variants of new description, associated all of them to a higher risk of developing PDB and distributed in different structural and functional domains of the p62 protein. References [1]Alonso, N., et al. Clinical Reviews in Bone and Mineral Metabolism, 2017;15(1),37–48. [2]Rea SL, et al. J Bone Miner Res. 2009;24(7):1216–23 [3]Visconti MR, et al. J Bone Miner Res. 2010;25(11):2368–73 [4]Falchetti A, et al. J Bone Miner Res. 2004;19(6):1013–7. Disclosure of Interests None declared